BACKGROUND: COVID-19 vaccines significantly reduce severe disease outcomes, but uncertainty remains about long-term protection. We investigated vaccine effectiveness (VE) against SARS-CoV-2 infection over extended periods in the World Health Organisation AFRO-MoVE network studies in Africa. METHODS: Participants with COVID-19-like symptoms were recruited between 2023 and 2024 for a test-negative case-control study conducted across 19-healthcare centres in Uganda. Cases were symptomatic patients with any three of cough, sore-throat, coryza, among others, and PCR-confirmed SARS-CoV-2, while controls were SARS-CoV-2 PCR-negative. Vaccination was verified from vaccination cards, hospital-records, vaccination registry and self-reporting. VE was assessed through three measures: (a) Annual - patients vaccinated in the past 12-months regardless of dose vs those vaccinated >12-months before symptom onset plus unvaccinated; (b) Absolute - patients vaccinated in the past 12-months vs unvaccinated; and (c) Relative - patients vaccinated in the past 12-months vs those vaccinated >12-months before symptom onset. VE was calculated as 1- adjusted odds ratio for three patient groups based on days since the last dose; (1) <365, (2) 7-269 and (3) 270-364 while adjusting for age, sex, calendar-time and chronic conditions. The sensitivity analysis excluded patients that were previously infected with SARS-CoV-2. FINDINGS: In total, 1371 patients, 56 % female were recruited. Of these, 173 were classified as cases, with 97 (56 %) fully vaccinated compared to 701 (59 %) controls, p = 0.830. The overall adjusted VE was moderate, 45 % to 59 %, and remained consistent across the annual, absolute and relative measures. Sensitivity analysis showed consistently lower VE (32 % to 38 %) across all measures. INTERPRETATION: The results suggest that COVID-19 vaccination provides moderate protection against symptomatic SARS-CoV-2 infection up to 12-months after the last dose and highlight the importance of up-to-date vaccinations for high-risk individuals. The lack of clear COVID-19 seasonality in this and other African settings creates a challenge to selecting the optimal timing for annual vaccination.